Laminin is a heterotrimeric, extracellular matrix (ECM) protein that has been implicated in mediating various aspects of cell function and survival. We have recently found that laminin is highly expressed in the mouse hippocampus, and that proteolytic degradation of this protein can promote the death of neurons. In this application, we propose a systematic exploration of the expression and function of laminin in the central nervous system (CNS). Specifically, we will determine the isoform(s) of laminin that is expressed in the hippocampus, identify the proteases directly responsible for its degradation and their sites of cleavage, and establish which region of laminin interacts with neurons to promote survival. Armed with this information, we will produce conditional knockout mice that lack the specific CNS laminin isoforms only in the hippocampus. These experiments will define the molecular characteristics and functional role of a critical ECM component in the mammalian CNS.